Prostate cancer (PCA) incidence and mortality rates vary widely among races in the United States. Among all men, PCA is the most commonly diagnosed form of cancer, but Native American men suffer a nearly two-fold higher rate of PCA mortality than whites following diagnosis. The extent of this disparity is not mirrored by other common cancer types, suggesting a unique burden of PCA-associated mortality in Native American men. Among the Navajo, PCA is more often diagnosed at a stage when the cancer has extended beyond the margins of the prostate (17.9% of PCA diagnoses among the Navajo, 3.3% among non-Hispanic Whites in New Mexico).These data underscore the need to understand the molecular mechanisms underlying clinically aggressive prostate cancer in all men, and Native Americans in particular. Among all races, PCA is highly heterogeneous and can vary from latent localized disease that does not require active treatment to aggressive disease associated with a high risk of mortality. Our goal is to better understand the genetic and molecular correlates of aggressive PCA. Our experimental approach will allow us to characterize genetic risk factors of particular importance to Native American populations. Previous studies have identified numerous somatic and germline genetic variants that increase risk for aggressive PCA. Of particular importance are mutations that affect the dosage of the tumor suppressor gene PTEN. Deletion of one PTEN allele occurs in 20-40% of localized PCA cancers and ~60% of metastases. Recent evidence also shows that PTEN protein loss occurs in 45% of primary tumors in the absence of deletion mutations, suggesting alternative mechanisms by which PTEN silencing is affected. Our proposed study will focus on the role of microRNA-mediated (mlRNA) regulation of PTEN, which is a critical regulatory mechanism for this tumor suppressor gene. Specifically, we will identify and analyze variants in miRNA response elements of PTEN and its expressed pseudogene, PTENP1. These two genes engage in regulatory crosstalk mediated by competition for miRNAs, such that allelic variations in PTENP1 can affect indirectly the expression of PTEN. This research extends the findings of our Pilot Project which found PTEN to be affected by allelic variation in miRNA interaction networks, and identified specific genetic variants in the miRNA response elements of PTEN that are unique to Native Americans. We propose a general model whereby germline genetic variants in the miRNA response elements of PTEN/PTENP1 3'UTR perturb competing endogenous RNA networks and function as modifiers of aggressive features of PCA.